Hyaluronan-directed fabrication of co-doped hydroxyapatite as a dual-modal probe for tumor-specific bioimaging

In recent years, nano-hydroxyapatite (nHAp) based dual-/multi-modal bioimaging systems have received significant attention due to their excellent bioactivity and biocompatibility. Specifically, co-doping two or more ions (such as Eu3+, Te3+, Gd3+ and Mn2+) into the lattice of nHAp can directly endow nHAp with multimodal imaging properties. However, the main strategy for the construction of co-doped nHAp nanocrystals depends on high temperature and techniques of post-modification, which could lead to inevitable nHAp crystal polymerization and increased particle size. Thus, the complexity of the preparation could further limit the clinical applications. Herein, based on the specific binding between hyaluronan and CD44 protein, a biomimetic synthesis method using hyaluronan as a template was explored for the construction of Eu/Ba co-doped and F-substituted nHAp (HA@nFAp:Eu/Ba) with recognition capability. The as-prepared HA@nFAp:Eu/Ba nanocrystals possessed uniform and spindle-like morphology with good monodispersity. Compared with co-doped nFAp that was synthesized under hyaluronan-free and high-temperature hydrothermal conditions, this one-step synthesized HA@nFAp:Eu/Ba presented improved doping efficiency and colloidal stability, realizing high sensitivity in both CT and fluorescence imaging. Besides, cytotoxicity studies indicated that the developed HA@nFAp:Eu/Ba nanocrystals exhibited good compatibility in both cells and mice. Meanwhile, the HA@nFAp:Eu/Ba nanocrystals also demonstrated tumor targeted stability in both cancer cells and living mice according to the favourable results from CT and fluorescence imaging. Therefore, this biomimetic synthesis strategy allowed multi-functionalization of nHAp in one pot under mild conditions.